Cortical potentials related to assessment of pain intensity with visual analogue scale (VAS)

Clinical Neurophysiology 113 (2002) 1013–1024 www.elsevier.com/locate/clinph

Cortical potentials related to assessment of pain intensity with visual analogue scale (VAS) Masutaro Kanda a,b, Masao Matsuhashi a, Nobukatsu Sawamoto a, Tatsuhide Oga a, Tatsuya Mima a, Takashi Nagamine a, Hiroshi Shibasaki a,c,* a

Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine and Faculty of Medicine, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan b Department of Neurology, Takeda General Hospital, Kyoto, Japan c Department of Neurology, Kyoto University Graduate School of Medicine and Faculty of Medicine, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan Accepted 18 April 2002

Abstract Objectives: To elucidate brain mechanisms underlying the psychophysical processes to measure pain intensity, pain-related somatosensory evoked potentials (pain SEPs) following painful CO2 laser stimulation were studied while employing a task to measure intensity of pain on a visual analogue scale (VAS). Methods: In 12 healthy subjects, 3 kinds of CO2 laser stimuli, different in intensity as determined by irradiation duration of 40, 60 and 80 ms, were randomly delivered to the left hand dorsum at an irregular interval of 4–6 s. The subject was requested to assess the intensity of each pain stimulus and point to the VAS scale by moving a pointer held with the right hand according to the subjective feeling of pain sensation (pain intensity assessment (PIA) condition). For the control condition, the subject moved the pointer to the midpoint of the VAS line irrespective of the pain intensity (control motor task condition). Electroencephalograms were recorded from 21 scalp electrodes, referenced to the linked earlobes, and were averaged time-locked to the stimulus onset for each stimulus duration as well as for each task condition. Results: The VAS scores were 2:8 ^ 0:5=10 for the stimulus of 40 ms duration, 4:8 ^ 0:8=10 for 60 ms and 6:1 ^ 0:9=10 for 80 ms, and showed a highly significant positive correlation with the stimulus duration. Following the early components of pain SEPs which were affected by stimulus duration but not modulated by task conditions, a surface-positive peak at latency of 612–642 ms was identified exclusively under the PIA condition regardless of the stimulus intensity and was called ‘intensity assessment-related potential (IAP)’. The IAP was maximal at the midline parietal area and symmetrically distributed over the scalp. Neither latency nor amplitude of the IAP was significantly different among the 3 different stimulus intensities. Conclusions: IAP is an event-related potential (ERP) associated with assessment of pain intensity but not influenced by pain intensity itself. From its scalp distribution, it can be assumed that the assessment of pain intensity involves multiple areas in both hemispheres. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pain intensity assessment; Visual analogue scale (VAS); CO2 laser stimulation; Pain-related somatosensory evoked potentials (pain SEPs); Eventrelated potentials (ERPs)

1. Introduction Throughout the philosophical and scientific history, it has been recognized that pain is formed of dual dimensions of sensory properties; intensity and unpleasantness (Gracely, 1999). Based on an assumption that subjects can meaningfully quantify the pain sensation on a psychological scale of pain magnitude (Price et al., 1983; Gracely, 1999), the intensity and the hedonic component (unpleasantness) of * Corresponding author. Tel.: 181-75-751-3601; fax: 181-75-751-3202. E-mail address: [email protected] (H. Shibasaki).

pain can be assessed separately with the aid of visual analogue scale (VAS), depending on the dimension of interest (Price et al., 1983, 1987; Olsen et al., 1992; Gracely, 1999). Thus, VAS has been commonly used as one of the self-rating scores of subjective pain intensity in clinical as well as experimental settings (Ohnhaus and Adler, 1975; Carlsson, 1983; Price et al., 1983; Olsen et al., 1992; Gracely, 1999). Painful stimulation with short pulse CO2 laser was introduced in pain research (Mor and Carmon, 1975), which, unlike electric shock, activates nociceptive receptors selectively and generates pure pain sensation (Bromm et al.,

1388-2457/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(02)00125-6

CLINPH 2001179

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1984). There has been an accumulation of studies on painrelated somatosensory evoked potentials (pain SEPs) following painful CO2laser stimulation (Carmon et al., 1976, 1978, 1980; Bromm and Treede, 1987; Treede et al., 1988; Kakigi et al., 1989; Miyazaki et al., 1994; Xu et al., 1995; Kanda et al., 1996a,b, 1999). Two components of pain SEPs, a negative peak (N2) followed by a positive one (P2), have been identified maximally at the midline central area at latencies of 200–300 ms following hand stimulation (Carmon et al., 1976, 1978, 1980; Bromm and Treede, 1987; Treede et al., 1988; Kakigi et al., 1989; Miyazaki et al., 1994; Xu et al., 1995; Kanda et al., 1996a,b, 1999). Carmon et al. (1978, 1980) found a positive correlation between the amplitude of the positive component of pain SEPs and the verbal report of pain. Garcı´a-Larrea et al. (1997) found a significant correlation between subjective intensity perception and the amplitude of pain SEPs when subjects attended the stimulus, although the stimulus intensity was kept constant. Pain VAS was also used when recording pain SEPs (Kakigi, 1994; Plaghki et al., 1994; Watanabe et al., 1996; Lorenz et al., 1997a,b). Kakigi (1994) found that the degree of pain relief was significantly correlated with changes in pain SEPs, particularly a marked decrease in the pain SEP amplitude and a decrease in VAS. Plaghki et al. (1994) found that both the VAS scores and the pain SEPs were affected by heterotopic nociceptive conditioning such as submerging hand in cold water. Watanabe et al. (1996) found that noxious cooling of the skin markedly decreased amplitude of pain SEPs and VAS scores. Lorenz et al. (1997a) reported that the pain VAS score and the amplitude of pain SEPs were reduced under morphine in patients with chronic non-malignant pain. Whereas these reports showed a correlation between the amplitude of the positive component of pain SEPs and the VAS scores, they did not refer to a possible component of pain SEPs related to actual processes executing the VAS for measurement of pain intensity. To our knowledge, there has been only one article focusing on this particular issue. Becker et al. (2000) reported that late potentials of SEPs were related to the execution process of VAS for pain intensity, although strong electric shocks, but not the selective nociceptive stimuli such as CO2 laser, were used as painful stimulus in their study. In the previous studies of pain SEPs using an oddball paradigm, a late positive peak following the P2 was identified as an oddball component occurring exclusively in response to the target (rare) stimuli, which were applied to either the radial or ulnar side of the hand dorsum while those for standards (frequent stimuli) were given to the remaining side (Towell and Boyd, 1993; Kanda et al., 1996a). Both groups of these authors demonstrated that neither N2 nor P2 was different between standard and target stimuli. In another study of ours using pain SEPs, we found a late positive peak following the P2 when the subject was instructed to identify each stimulated spot (Localization Potential: LP). Since the task required ‘point localization’ of each pain stimulus, which is a kind of cortically dependent sensation, we

concluded that LP was related to the somatotopic localization of pain (Kanda et al., 1999). In view of these previous studies of event-related potentials (ERPs) using pain stimulus, we hypothesized that, when a subject was instructed to evaluate intensity of CO2 laser stimulus with VAS, psychophysical processes involved in the task would generate ERPs that could be specifically related to the evaluation of pain intensity. In this study, therefore, pain SEPs were recorded using CO2 laser stimuli of various intensities, while the subject was required to measure subjective intensity of pain evoked by the stimuli on VAS. The effects of this task on the N2 and P2 were also examined.

2. Methods 2.1. Subjects Twelve normal subjects (11 males and one female; age 27:1 ^ 5:2 (mean ^ SD) years; all right-handed) volunteered for this study. Each subject gave informed consent in a written form before the experiment according to the Declaration of Helsinki. The subject was seated in a reclining armchair in a quiet and electrically shielded room, with the ambient temperature controlled at about 248C. They were instructed to keep their eyes open as much as possible during the recording session.

2.2. Pain stimulus Pain stimuli were delivered by means of a special CO2 laser stimulator (Nippon Infrared Industries Co. Ltd, Kawasaki, Japan) (Miyazaki et al., 1994; Xu et al., 1995; Kanda et al., 1996a,b, 1999, 2000). The use of this instrument was approved by the Committee of Medical Ethics of Graduate School of Medicine and Faculty of Medicine, Kyoto University. The laser wavelength was 10.6 mm, and its constant power output was 6 W, while the irradiation beam was adjusted to 6 mm in diameter on the skin with the aid of a helium–neon laser (Kakigi et al., 1989; Miyazaki et al., 1994; Xu et al., 1995; Kanda et al., 1996a,b, 1999). Stimuli were presented to the dorsum of the left hand in all subjects, and, in addition, also to that of the right hand in 6 out of the 12 subjects. The interstimulus interval varied randomly between 4 and 6 s. Duration of each CO2 laser irradiation was randomly set to 40, 60 or 80 ms. The calculated energy was approximately 8.5, 12.7 and 17.0 mJ/mm 2 for these 3 kinds of stimuli, respectively. The stimulation was controlled with the aid of STIM software (Neurosoft Inc., Virginia, USA). Each stimulus elicited a painful sensation like a ‘pinprick’ at least to some extent in normal subjects irrespective of the energy of the given stimulus. Subjects’ eyes were protected with glasses against dispersion of the beam.

M. Kanda et al. / Clinical Neurophysiology 113 (2002) 1013–1024

2.3. Task conditions 2.3.1. Pain intensity assessment (PIA) condition For the VAS, a 50 cm long horizontal line was drawn on a screen placed 1.5 m in front of the subject. The line had 10 scales at a regular interval and was labeled ‘no pain’ at the left end and ‘the most intense pain imaginable’ at the right. The subject held a laser pointer with the non-stimulated hand and pointed to the left end of the VAS line. In response to each CO2 laser stimulus, the subject was requested to point to an appropriate spot on the VAS line for the pain intensity (PIA task). The subject was asked to evaluate the subjective intensity of each pain stimulus into 10 grades, instead of categorizing each given stimulus into 3 kinds of CO2 laser stimuli; ‘weak’, ‘medium’ and ‘strong’. The value of the VAS was then read visually by one of the experimenters. When instructing the subject before the experiment, precision of pointing to the corresponding spot on the VAS was emphasized rather than the speed of response. The subject then returned the laser pointer slowly to the left end of the VAS line. If the subject did not move the laser pointer within 1 s after stimulus, the performance was considered unsatisfactory. 2.3.2. Control motor task condition In the control motor task condition, the subject held a laser pointer in the same way as in the PIA condition, but was instructed to point to the middle point of the VAS line in response to all stimuli, irrespective of the pain intensity. The subject then returned the laser pointer slowly to the starting point. Under this condition, therefore, the subject was not required of any evaluation of pain intensity. Unsatisfactory performance was the same as that defined for the PIA condition. 2.3.3. Control rest condition Under the control rest condition, pain stimuli were given just like in the other two conditions, but the subject was simply requested to stay still with the eyes kept open. Like the control motor task condition, the subject did not need any evaluation of pain intensity under this condition. Thus, neither PIA nor motor response was required in this condition. 2.4. Experimental design One session consisted of 5 blocks of stimuli, each block consisting of 3 CO2 laser stimuli of different intensity levels determined by 3 different irradiation duration (40, 60 and 80 ms). While the sequence of the 3 kinds of stimuli within each block was randomly arranged, the order of the blocks within each session was also randomly changed from session to session. Six sessions were tested for each of the PIA, the control motor and the rest condition, so that 90 stimuli were presented for each condition. Among the overall 18 sessions given to each subject, the control rest condi-

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tion was tested during the first 3 and the last 3 consecutive sessions. In the remaining 4th to 15th sessions, 3 consecutive sessions were given for each of the other two conditions (PIA and control motor) alternately, while the order of these two conditions was counterbalanced across subjects. In the 6 subjects in whom the right hand was also tested, these 3 conditions were tested in the same way as for the left hand. 2.5. Data acquisition In all subjects, Electro-Cap (Electro-Cap International Inc., Ohio, USA) with tin electrodes was used to record electroencephalograms (EEGs) from the scalp. Electrode arrangement was Fp1, Fpz, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, Oz and O2 according to the International 10–20 System, all referenced to linked earlobes. The ground electrode of the Electro-Cap was located mid-way between Fpz and Fz. For monitoring artifacts arising from blinks and vertical eye movements, an electrode placed 1 cm below the right eye was referenced to another electrode placed just above that eye. For monitoring artifacts from horizontal eye movements, an electrode placed 1 cm lateral to the left outer canthus was referenced to another electrode placed 1 cm lateral to the right outer canthus. In 3 subjects, surface electromyograms (EMGs) were recorded from the right extensor carpi radialis muscle by placing a pair of electrodes on the muscle belly 3 cm apart from each other. These 6 electrodes were also made of tin. All electrodes were filled with electro-conductive jelly, and the impedance was maintained at less than 5 kV. Potentials were amplified with the band pass range from direct current (DC) to 50 Hz (23 dB) for EEGs and 10–50 Hz (23 dB) for EMGs, which were digitized at a rate of 400 Hz, using SYNAMP and SCAN software (Neurosoft Inc., Virginia, USA). 2.6. Averaging For all conditions, an EEG epoch of 2.0 s including the prestimulus period of 200 ms was analyzed. For the PIA and the control motor task conditions, the epoch in which task performance was unsatisfactory was discarded. For each epoch, the baseline was corrected using an average of EEG data during the prestimulus period for each channel, and the linear trend of DC shift was corrected. Epochs contaminated by blinks and/or eye-movement artifacts, as well as those containing potentials exceeding ^40 mV from the baseline, were excluded from analysis. In each session, epochs in response to 3 different kinds of stimuli in terms of duration (40, 60 and 80 ms) were separately collected. 2.7. Data analysis After confirming the reproducibility of each waveform across sessions with respect to the condition (PIA and two controls) as well as to the stimulus duration (40, 60 and 80 ms), the average for each condition/duration combina-

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tion was obtained with respect to the stimulus onset, so that overall 9 sets of averaged waveforms were obtained for each subject. In 6 of the 12 subjects in whom the right hand was also examined, another 9 sets of averaged waveforms for the right hand were also obtained. Amplitude of each identified component was measured from the baseline (determined as described above). In the 3 subjects in whom EMGs were recorded, the onset of synchronous discharges of rectified EMGs was measured as the reaction time under PIA and control motor task conditions, and the data were averaged for each stimulus duration for each condition, so that 6 sets of averaged reaction time were obtained. For analyzing the latency and amplitude of each component under all the 3 conditions, two-way analyses of variance (ANOVAs) with repeated measurements were performed by the use of the within factors of condition and stimulus duration. Regarding the component obtained only in the PIA condition, a one-way ANOVA with repeated measurements was performed for its latency and amplitude by the use of the within factor of stimulus duration. As for effects of the side of stimulation for the 6 subjects in whom both hands were studied, two-way ANOVAs with repeated measurement were performed for its peak latency and amplitude by the use of the within factors of stimulated hand and stimulus duration. For topographic analyses of components obtained in all 3 conditions, 3-way ANOVAs with repeated measurements were performed by the use of the within factors of condition, stimulus duration and electrode site. Regarding the component identified only in the PIA condition, a two-way

ANOVA with repeated measurements was performed by the use of the within factors of stimulus duration and electrode site. In the 6 subjects in whom both hands were studied, a 3-way ANOVA with repeated measurements was performed to examine the effect of stimulated side by the use of the within factors of stimulated hand, stimulus duration and electrode site. In order to reduce the problem that the ANOVA model, which is based on an additive assumption, can lead to misinterpretation of amplitude distribution, the amplitude at each electrode location was divided by the combination set specific vector length (vector normalization) (McCarthy and Wood, 1985; Naumann et al., 1992). The vector length was defined by the square root of the sum of squared amplitudes over all electrode locations, which was calculated separately for each of the 9 sets of condition/duration combination in all subjects and for each of the 18 sets (condition/duration/stimulated hand) in 6 of them. The significance level was set at P , 0:05. In addition to ANOVAs, normalized data were also used to make contour maps of the component obtained only in the PIA condition for the 3 kinds of stimulus duration, by using Matlab 6.1 with biharmonic spline interpolation (Mathworks Inc., Natrick, MA, USA). 3. Results 3.1. Behavioral data In each subject, the intensity values measured by the VAS were classified into 3 groups according to the duration of the given stimulus. The mean VAS scores for each of the 3 stimulus groups for each subject are shown in Fig. 1. The mean VAS scores among all subjects were 2:8 ^ 0:5 for the stimulus of 40 ms duration, 4:8 ^ 0:8 for 60 ms, and 6:1 ^ 0:9 for 80 ms. Linear regression analysis was used to determine the correlation between the stimulus duration (x-axis) and the VAS scores (y-axis), and showed a highly significant positive correlation (y ¼ 0:088x 2 0:741, r ¼ 0:93, P , 0:0001). The reaction times averaged among 3 subjects under the PIA condition were 586.7 ms for the stimulus duration of 40 ms, 587.3 ms for 60 ms and 562.3 ms for 80 ms, and those under the control motor condition were 478.3, 447.3 and 450.2 ms for these 3 stimulus durations, respectively. 3.2. Waveforms of pain SEPs

Fig. 1. Relation between the stimulus duration and the VAS scores. While the VAS scores were classified into 3 groups according to the stimulus duration (40, 60 and 80 ms) of the CO2 laser pulses, the mean value of each group for each subject was plotted against the stimulus duration. Linear regression analysis was used to determine the relation between the stimulus duration (x-axis) and the VAS scores (y-axis), which showed a highly significant positive correlation (y ¼ 0:088x 2 0:741, r ¼ 0:93, P , 0:0001).

The mean numbers of single trials subjected for averaging under the PIA condition per subject were 25:6 ^ 4:0 for the stimulus duration of 40 ms, 24:9 ^ 5:6 for 60 ms and 23:2 ^ 5:1 for 80 ms, those under the control motor task condition were 24:3 ^ 4:1, 23:4 ^ 5:9 and 22: 7 ^ 6:4, and those under the control rest condition were 25:4 ^ 4:8, 24:2 ^ 5:6 and 23:3 ^ 6:0, each for these 3 kinds of stimulus duration, respectively. ANOVAs with repeated measurements showed no effect of condition (F 2;22 ¼ 0:439, P ¼ 0:612),

M. Kanda et al. / Clinical Neurophysiology 113 (2002) 1013–1024

stimulus duration (F2;22 ¼ 1:623, P ¼ 0:220) or their interaction (F4;44 ¼ 0:271, P ¼ 0:854). Waveforms obtained from a representative subject under the 3 conditions (PIA, control motor task and control rest) for the 3 kinds of stimulus duration (40, 60 and 80 ms) are shown in Fig. 2. Early negative–positive peaks (N2–P2) were identified in the averaged waveforms of pain SEPs for all 9 sets of condition/duration combinations. Following these potentials, a positive deflection was observed maximally at Pz only under the PIA condition for the stimulus duration of 40–60 ms (Fig. 2). This PIA-related potential is called ‘intensity assessment-related potentiar‘ (IAP) in this paper. The peak latency of IAP was 602 ms for the stimulus duration of 40 ms and 646 ms for 60 ms. The peak amplitudes of IAP for the two stimulus durations were 9.3 and 8.0 mV, respectively. Grand average data across all subjects for each of the 3 conditions for the stimulus duration of 40 ms are shown in Fig. 3. The early negative–positive peaks (N2–P2) were clearly recognized in all conditions. The latencies of N2 and P2 were similar among the 3 conditions. After the P2, another positive component (IAP) was detected exclusively in the PIA condition. IAP was largest at Pz electrode. A relatively steep negative-going slope (NS 0 ), which started immediately after P2, was seen over the central electrode only in the control motor task condition, indicating that this activity is movement-related (Neshige et al., 1988). Similar results for the N2, P2, NS 0 and IAP were obtained from the data for the stimulus duration of 60 and 80 ms (data not

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shown). The peak latency of IAP was 602 ms for the stimulus duration of 40 ms, 649 ms for 60 ms and 624 ms for 80 ms. 3.3. Component related to PIA (IAP) Measurement of IAP was done at Pz electrode where it was largest. The mean peak latency and amplitude of IAP among all subjects for each of the 3 stimulus durations are shown in Fig. 4. The mean peak latencies of IAP were 642 ^ 64 ms for the stimulus duration of 40 ms, 612 ^ 92 ms for 60 ms and 619 ^ 76 ms for 80 ms, and their amplitudes were 8:2 ^ 4:2, 7:1 ^ 5:7 and 9:4 ^ 5:6 mV, respectively. ANOVAs showed no effect of stimulus duration (d) on the latency or amplitude of IAP (Table 1). With respect to the 6 subjects in whom both hands were studied, there was no effect of stimulated hand on the latency or amplitude of IAP (F1;5 ¼ 0:303, P $ 0:05; F1;5 ¼ 0:001, P $ 0:05, respectively). Contour maps of IAP after vector normalization are shown in Fig. 5. IAP was maximal at Pz and symmetrically distributed for all 3 kinds of stimulus duration. ANOVA showed a significant effect of electrode site (s) on the normalized amplitude of IAP, but no effect of stimulus duration (d) on it (Table 2). There was no interaction between electrode site and stimulus duration (ds) (Table 2). In the 6 subjects in whom both hands were studied, there was no effect of stimulated hand on the scalp distribution (F1;5 ¼ 0:031, P $ 0:05).

Fig. 2. Waveforms of pain SEPs for 3 different stimulus durations obtained from a subject in the PIA (red line), control motor (green line) and control rest (black line) conditions. Left hand stimulation. Early negative–positive peaks (N2–P2) are recognized in all 9 sets of condition/stimulus duration combinations. Following these peaks, a positive deflection is observed maximally at Pz only in the PIA condition for the stimulus duration of 40 and 60 ms, which is called IAP.

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Fig. 3. Grand average waveforms, shown at all electrodes, across all subjects obtained in the PIA (red line), control motor task (green line) and control rest (black line) condition. Stimulus duration 40 ms. Left hand stimulation. N2 and P2 are equally recognized in all conditions. Only in the PIA condition, a positive component is seen following P2 (IAP). A negative slope (NS 0 ) is seen only in the control motor task condition.

3.4. N2 of pain SEPs For 3 sets of data corresponding to the 3 conditions (PIA, control motor task and control rest), the mean values of peak latency and amplitude of N2 and P2, measured at Cz electrode, among all subjects for each of the 3 stimulus durations are shown in Fig. 6. The latency of N2 was around 245 ms for all conditions as well as for all stimulus durations (244 ^ 28, 245 ^ 19 and 252 ^ 26 ms for the stimulus duration of 40, 60 and 80 ms, respectively) (Fig. 6A). ANOVA showed no effect of condition (c), stimulus duration (d) or their interaction (cd) on the latency of N2 (Table 1). The amplitude of N2 was smallest for the stimulus duration of 40 ms ð25:4 ^ 3:4 mVÞ, largest for 80 ms ð29:2 ^ 5:0 mVÞ and intermediate for 60 ms ð28:6 ^ 4:4 mVÞ, in all 3 conditions (Fig. 6B). There was a significant effect of

stimulus duration (d) on the amplitude of N2, but no effect of condition (c) or its interaction (cd) (Table 1). On the scalp distribution of N2, there was a significant effect of electrode site (s), but no effect of condition (c) or stimulus duration (d) (Table 2). None of the interactions of these terms (cd, cs, ds or cds) was significant. 3.5. P2 of pain SEPs The latency of P2 for the stimulus duration of 40 ms was shortest ð357 ^ 33 msÞ, that for 80 ms was longest ð385 ^ 46 msÞ and that for 60 ms was in between ð367 ^ 39 msÞ (Fig. 6C). The amplitude of P2 was smallest for the stimulus duration of 40 ms ð8:4 ^ 5:3 mVÞ, largest for 80 ms ð12:1 ^ 5:8 mVÞ and intermediate for 60 ms ð10:6 ^ 5:1 mVÞ in all 3 Table 1 ANOVA results for the effects of condition and stimulus duration on amplitude and latency of IAP, N2 and P2 a Component

Factor (d.f.)

F-value Latency

Fig. 4. Mean peak latency (A) and amplitude (B) of IAP across all subjects along with their standard deviations (vertical bars) plotted against the 3 kinds of stimulus duration (40, 60 and 80 ms).

Amplitude

IAP

d (2,22)

0.752

2.650

N2

c (2,22) d (2,22) cd (4,44)

1.088 2.498 0.576

0.140 17.107*** 1.021

P2

c (2,22) d (2,22) cd (4,44)

2.842 5.721* 2.427

0.435 5.352* 1.131

a Abbreviations of ANOVA terms: c, condition; d, stimulus duration. Significance values were obtained using Greenhouse–Geisser correction: *P , 0:05; **P , 0:01; ***P , 0:001.

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Fig. 5. Contour maps of IAP for the 3 kinds of stimulus duration (40, 60 and 80 ms), obtained by using Matlab 6.1 with biharmonic spline interpolation (Mathworks Inc., Natrick, MA, USA). Amplitudes of the component obtained only in the PIA condition were measured at all electrodes and used after vector normalization. IAP is maximal at Pz and symmetrically distributed regardless of the stimulus duration.

conditions (Fig. 6D). ANOVAs showed a significant effect of stimulus duration (d) on the latency and amplitude of P2, but no effect of condition (c) on either of them (Table 1). There was no significant interaction between condition and stimulus duration (cd). On the scalp distribution of P2, there was a significant effect of electrode site (s), but no effect of condition (c) or stimulus duration (d) (Table 2). None of the interactions of these terms (cd, cs, ds or cds) was significant. 3.6. Correlation between stimulus duration/pain intensity and pain SEP

and amplitude of P2 were significantly related to the stimulus duration, while the population of the stimulus duration lacked normality of distribution. Thus, it was considered reasonable to calculate Spearman correlation coefficients to further evaluate correlation between the stimulus duration and each of these significant parameters. As the results, the amplitude of N2 showed a positive correlation with the stimulus duration (Spearman r ¼ 20:373, N ¼ 108, P , 0:001). Both the latency and amplitude of P2 showed significant correlations with the stimulus duration (r ¼ 0:254, N ¼ 108, P , 0:01; r ¼ 0:278, N ¼ 108, P , 0:01, respectively).

As described above, the amplitude of N2 and the latency Table 2 ANOVA results for the effects of condition, stimulus duration and electrode site on scalp distribution of IAP, N2 and P2 a Component

Factor (d.f.)

F

IAP

d (2,22) s (20,220) ds (40,440)

0.007 5.280* 1.702

N2

c (2,22) d (2,22) s (20,220) cd (4,44) cs (40,440) ds (40,440) cds (80,880)

0.148 0.038 11.805** 0.026 1.354 0.859 0.868

P2

c (2,22) d (2,22) s (20,220) cd (4,44) cs (40,440) ds (40,440) cds (80,880)

0.017 0.020 17.990*** 0.005 1.925 0.855 0.737

a Abbreviations of ANOVA terms: c, condition; d, stimulus duration; s, electrode site. Significance values were obtained using Greenhouse–Geisser correction: *P , 0:05; **P , 0:01; ***P , 0:001.

3.7. Correlation between VAS scores and pain SEP Amplitude of N2–P2 complex was calculated as the peak amplitude of P2 measured from the N2 peak, and Pearson correlation coefficient calculated between these values and the VAS scores, both showing normality of distribution for their population, and a positive correlation between the two (r ¼ 0:428, N ¼ 36, P ¼ 0:009). Pearson correlation coefficients were calculated between the VAS scores and the latency of IAP as well as between the former and the IAP amplitude, and neither showed any correlation (r ¼ 20:065, N ¼ 36, P ¼ 0:707; r ¼ 20:022, N ¼ 36, P ¼ 0:899, respectively).

4. Discussion The present study conformed to the two major recommendations for pain research suggested by Bromm (1995), consisting of: (1) randomized stimulus intensities and (2) subjective rating for each pain sensation. However, against the Bromm’s recommendation that the interstimulus interval should be preferably between 10 and 20 s (Bromm, 1995; Scharein and Bromm, 1995), the interstimulus inter-

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Fig. 6. Mean peak latency (A) and amplitude (B) of N2 and those of P2 (C and D, respectively) across all subjects along with their standard deviations (vertical bars) in PIA (circle), control motor (square) and control rest (triangle) conditions plotted against the stimulus duration of 40, 60 and 80 ms. Stimulus duration had effects on the peak latency of P2 and amplitude of N2 and P2 but not on the peak latency of N2, whereas experimental condition did not affect N2 or P2 in terms of peak latency or amplitude.

val employed in the present study was about a half of it. In our previous reports on ERPs using CO2 laser stimulation (Kanda et al., 1996a, 1999), this relatively short interstimulus interval was used because it could shorten the recording period so that the subject could reduce the amount of blinks and eye movements to a minimal and keep vigilance level throughout the recording. Thus we employed a relatively short interstimulus interval also in the present study. 4.1. Cortical response related to assessment of pain intensity As the main finding of this study, a late positive component, which was called IAP, was recognized at around 600 ms after painful stimulation exclusively in the PIA condition. Since the subject was requested to do the same motor task in both the PIA and the control motor task conditions, the only difference between the two conditions was that the former involved the psychophysical processes to measure pain intensity on the VAS while the latter did not. Moreover, neither latency nor amplitude of IAP was influenced by the intensity of pain stimulus itself, which was varied by changing the stimulus duration in this study. Therefore, IAP is most likely related to the psychophysical processes of pain intensity assessment. The use of VAS is rationalized based on an assumption that subjects can meaningfully quantify the pain sensation

on a psychological scale of its magnitude (Price et al., 1983; Gracely, 1999). It is the existence of an actual stimulus, regardless of its intensity, that operates the psychophysical processes involved in the VAS for the sensory intensity dimension of pain. As described above, IAP was not different in latency, amplitude or scalp distribution among the 3 different levels of stimulus intensity, indicating that a single major factor for the generation of IAP is the existence of pain stimulus but not its given or perceived intensity. Thus it is possible that the IAP is one of the late positive components evoked by meaningful, task-relevant stimuli, which were previously reported by other researchers (Sutton et al., 1965; for review see e.g. Picton, 1992; Polich and Kok, 1995). The above features of IAP fulfill most of the requirements for an endogenous component of ERPs (Donchin et al., 1978, 1986; Johnson, 1988). As regards the negative component (NS 0 ) seen only in the control motor task condition, it occurred at least 50 ms earlier than the motor response as determined by surface EMGs. Thus, this activity seems to be in conformity with the previously reported NS 0 preceding self-initiated movement (Neshige et al., 1988). The corresponding activity was not recognized in the PIA condition, which involved the similar motor response. It is conceivable that the negative motor-related component might have been cancelled out by the simultaneously occurring positivity (IAP). One way to solve this problem is to employ mental evaluation of pain

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intensity without involving motor execution, but it was difficult to carry out PIA-like task under an imaginary condition. It may be possible that a potential like the present IAP would be also generated in association with other methods of pain intensity assessment such as verbal report of pain. However, vocalization necessarily accompanying the verbal report may generate artifacts in the analysis window when it is done within 1 s after the stimulus presentation. If it is done 1.8 s after the stimulus presentation when the present analysis period is over, then a process for memorizing the measured intensity of pain may be involved. Furthermore, evaluation with verbal report inevitably involves a task to compare the given pain with some instructed scale of pain intensity. These constraints make it difficult to record a potential like the IAP by using the verbal report. It may also be possible that an IAP-like potential might be generated for other modalities of sensory stimulus in relation to execution of the VAS. However, since generalization of the IAP was beyond the range of this study, other sensory modalities were not examined in this study. 4.2. Mechanism underlying the generation of IAP The peak latencies of IAP were similar to those of an oddball component P300 of our previous study in which pain SEPs were recorded while using an oddball paradigm (Kanda et al., 1996a). Therefore, a question arises as to whether the IAP is related to an oddball component or not. The P300 recorded in an oddball paradigm involves a categorization process to judge the target stimulus (Donchin et al., 1978, 1986; Johnson, 1988). However, in the present PIA condition, the instructions did not involve any categorization process such as classifying of each pain sensation into 3 levels such as weak, medium and strong. Furthermore, although the probability is one of the major independent factors that generate the P300 (Donchin et al., 1978, 1986; Johnson, 1988), probability for each of these 3 kinds of stimuli was 0.33. Even if an effect of probability was present on the potentials under the PIA condition, we used the same stimulus paradigm with the 3 kinds of intensity also under the control motor task condition. These imply that, while it is believed that the P300 represents contextupdating in ‘working memory’ (Donchin et al., 1986), the present IAP is unlikely to involve such process. Therefore, it seems reasonable to assume that the present IAP is distinguishable from the oddball P300. Polich (1998) stated in his review that P300 indexes the attentional and memoryrelated operations involved in the processing of that signal. In the present study, it was evident that the PIA condition included some memory-related operations in which pain intensity of a given stimulus was evaluated according to one’s own pain experience. Thus the possibility that the present IAP is a P300-like activity cannot completely be excluded. The IAP showed the midline parietal dominance (Fig. 5), conforming to the report by Becker et al. (2000) that the late

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potentials relating to measurement of pain intensity following electric shocks showed the midline parietal dominance. However, the difference between the present result and theirs is that we identified IAP as a peak while the latter investigators did not identify any isolated peak but instead studied the difference in waveform. This could be explained by the fact that in our study the pain system was selectively activated by CO2 laser stimulation while in their study strong electric shocks most likely affected other sensory modalities in addition to pain. The scalp distribution of IAP was similar to that of the oddball P300 using CO2 laser stimulus (Kanda et al., 1996a). Thus the late midline parietal positivity of the present IAP may not be specific for evaluation of pain intensity, although the physiological processes of the IAP are different from those of oddball P300. The midline parietal dominance of the oddball P300 is considered to be a summation of multiple generator sources symmetrically distributed in both hemispheres (Nishitani et al., 1998, 1999). Provided that similar mechanisms like an oddball P300 had participated in the generation of the IAP, the IAP might have been also generated from multiple generator sources, although these sources are expected to differ from those of the oddball P300. However, we cannot discuss generator sources of the IAP any further because the suitable technique for modeling its generator sources still remains to be developed. The IAP, like the LP in our previous study (Kanda et al., 1999), involved nociceptive-visuomotor transformation in its generation, although the control motor task condition contributed to reduce the possibility of these effects on the IAP. The IAP is also similar to the LP in terms of latency and polarity. Whereas the LP was maximal at Cz, the present IAP, like a pain-related P300 in our previous study (Kanda et al., 1996a), was maximal at Pz, suggesting that the distribution of the late component depends on the employed task but not just on the effects of nociceptivevisuomotor transformation. Therefore, it is postulated that the present IAP provides an opportunity to study physiological mechanisms underlying assessment of pain intensity. By using a similar task of point localization, Valeriani et al. (2000) reported not only the late parietal positive potential but also an early positive component of pain SEPs maximal at temporal electrodes contralateral to the stimulated side, which raised a possibility that some ‘hidden’ component would be uncovered by using a task to which the subjects concentrated his/her attention. However, no such early positive component was found in the present study or in our previous study on LP. One explanation for this discrepancy is that, in addition to a point localization task, their study involved an oddball paradigm while our studies did not. 4.3. Early cortical responses to pain stimulus The waveform of pain SEPs in the present study contained early peaks (N2 and P2), in agreement with the previous reports (Carmon et al., 1976, 1980; Bromm and

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Treede, 1987; Treede et al., 1988; Kakigi et al., 1989; Beydoun et al., 1993; Towell and Boyd, 1993; Miyazaki et al., 1994; Xu et al., 1995; Kanda et al., 1996a,b, 1999). In the present study, neither N2 nor P2 showed significant differences in the peak latency, amplitude or scalp distribution among the 3 experimental conditions (PIA, control motor and control rest), while N2 and P2 were previously reported to be modulated by attention, emotion and/or arousal state (Beydoun et al., 1993; Miyazaki et al., 1994; Zaslansky et al., 1996a,b; Garcı´a-Larrea et al., 1997; Yamasaki et al., 1999) or by morphine (Lorenz et al., 1997a,b). It is, therefore, likely that the conditions employed in the present study were independent of these modulatory factors. This is similar to our previous studies on pain SEPs by employing an oddball paradigm (Kanda et al., 1996a) and a localization task (Kanda et al., 1999), although Zaslansky et al. (1996b) reported that P2 was modified in an oddball paradigm. Regarding the latency of N2, it was around 245 ms irrespective of the experimental conditions as well as the stimulus duration. This latency was slightly longer than that of the first negative potential after the CO2 laser stimulation which was directly recorded from the primary somatosensory cortex (SI) (Kanda et al., 2000), second somatosensory cortex (SII) (Lenz et al., 1998b) and the anterior cingulate cortex (ACC) (Lenz et al., 1998a). The latency of the present N2 was also longer than that of any of the equivalent current dipoles (ECDs) estimated in the contralateral SI, and the contralateral and ipsilateral SII in our previous study using magnetoencephalography (MEG), which were 217, 212 and 213 ms, respectively (Kanda et al., 2000). Studies using positron emission tomography (PET) or functional MRI (fMRI) showed activation in multiple brain areas including the contralateral SI, the bilateral SII, ACC and insula, and the frontal lobe and thalamus contralateral to the stimulus side (Talbot et al., 1991; Derbyshire et al., 1997; Xu et al., 1997; Sawamoto et al., 2000). These suggest that multiple brain areas including SI, SII and ACC participate in the generation of N2. The present study showed that, while the peak latencies of P2 were shorter than 400 ms for all 3 kinds of stimulus duration, the reaction time was longer than 550 ms in the PIA condition and longer than 450 ms even in the control motor task condition. It is believed that the decision leading to a task precedes the process that generates potentials relevant to that task (Picton, 1992). Thus it is unlikely that the P2 involves the evaluation process for pain intensity. The present results of ANOVAs showed that the latency of P2 was affected by stimulus duration while that of N2 was not. By using PET, Derbyshire et al. (1997) reported that, while CO2 laser stimulation of just painful intensity showed activation of the contralateral prefrontal (area 10/46/44), bilateral inferior parietal (area 40) and ipsilateral premotor cortices (area 6), that of mild and moderate pain intensity showed extension of activated areas including the bilateral prefrontal, inferior parietal and premotor cortices and thala-

mus, the contralateral hippocampus, insula and SI, and the ipsilateral perigenual cingulate cortex (area 24) and medial frontal cortex (area 32). This extension of the activated areas in proportion to the increased stimulus intensity could explain why the peak latency of P2 was prolonged for the stronger intensity of the CO2 laser stimulus while the onset of the pain processing remained the same for any level of stimulus intensity. The present results showed main effects of stimulus duration on amplitudes of both N2 and P2, showing positive correlations between stimulus intensity and these peaks, in conformity with the previous reports (Carmon et al., 1976, 1978, 1980). The present study also showed a positive correlation between the amplitude of N2–P2 complex and the VAS score, also in accord with previous reports (Carmon et al., 1978, 1980; Kakigi, 1994; Plaghki et al., 1994; Watanabe et al., 1996; Lorenz et al., 1997a,b; Garcı´a-Larrea et al., 1997). However, the present study did not show any effect of stimulus intensity or its interactions on scalp distribution of N2 or P2. The electrode site showed an effect, but its interactions did not show any effect. These imply that, while the dimension of the activated areas by CO2 laser stimuli might be the same for the 3 kinds of stimulus duration, their extension might be proportional to the input intensity of pain stimulus.

5. Conclusions The present study by using VAS demonstrated late cortical potentials of pain SEPs related to assessment of pain intensity, which was called IAP. Pain intensity did not affect the peak latency, amplitude or scalp distribution of IAP. There was no correlation between the VAS scores and the latency or the amplitude of the IAP. These suggest that IAP is an endogenous component depending on the existence of pain stimulus but not its given or perceived intensity. The IAP showed midline parietal dominance and symmetric distribution, suggesting that assessment of pain intensity involves multiple areas in both hemispheres. As regards early components of pain SEPs; N2 and P2, neither of these two was modulated by experimental conditions but they were related to stimulus intensity, suggesting that they are related to processing of pain stimulus itself but not to evaluation of pain intensity.

Acknowledgements This work was supported by Grant-in-Aid for Scientific Research for Future Program JSPS-RFTF97L00201 from the Japan Society for the Promotion of Science, and Scientific Research (B) 13470134 and Priority Areas (C) Advanced Brain Science 12210012 from the Japan Ministry of Education, Science, Sports and Culture to H.S.

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